JPS5855151B2 - Method for dividing trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention describes certain trans-2=substituted-5-aryl-2.3.4.4a.5.
9b-Hexahydro-IH-pyrido[4.3-b) Intermediates for the production of indole derivatives.

■Four Toiso Publications filed on May 23, 1978 p.
2822465.9 has the formula [4a and 9b in the formula]
The hydrogen atoms added to the positions are in a trans relationship with each other: X1 and Yl are the same or different, each hydrogen or fluoro; n is 3 or 4; M is C(0) or CH (OH) and +21 is hydrogen, fluoro or methoxy.

] is disclosed and is said to have tranquilizer properties.

The inventors are 5-aryl-2, 3, 4, 4a, 5, 9
It has been found that compounds of formula (I) in which the b-hexahydro-1H-pyrido[4.3b] moiety is dextrorotatory have surprisingly advantageous properties.

5-Aryl-2.3.4.4a.5.9bhexahydro-IH-pyrido[4.3-b) The indole moiety refers to the moiety to the formula.

・[In the formula, the hydrogen atoms added to the carbon atoms at positions 4a and 9b are in a trans relationship with each other.

Among the compounds of formula (I), compounds in which the moiety of formula A is levorotatory have considerably low activity as tranquilizers.

Compounds of formula (1) in which the A moiety is dextrorotatory have a significantly and unexpectedly superior tranquilizer effect over the above-mentioned tranquilizers of the prior art.

This invention relates to a process for preparing dextrorotatory amines of formula (AH) useful for preparing compounds of formula I in which the A moiety is dextrorotatory from racemic mixtures thereof.

The tranquilizer prepared from intermediate CAH) according to the invention is represented by formula (I)'.

[In the formula, the hydrogen atoms added to the carbon atoms at positions 4a and 9b are in a trans relationship, and the aryl-2,3,4,4a,5,9b-hexahydro1H-pyrido[4,3-b]indole moiety (A ) is dextrorotatory, and Zl , n and M are as defined above.

] As will be clear to those skilled in the art, moiety (A) has two asymmetric carbons at positions 4a and 9b, with two resolved trans forms (d- and l-) and a racemic form Xl and Exists for each Y1.

Of course, part (A) does not exist alone; for example, the formula (
A-H) from the free base, from which compounds of formula (I) are obtained.

Compound (AH) has dextrorotatory (d-) enantiomer,
levorotatory (l-) enantiomer and equivalent amounts of d and l
- these two containing racemates containing enantiomers
Exists as a mixture of two enantiomers.

Dedextrorotatory and levorotatory isomers can be distinguished by their ability to rotate the plane of plane-polarized light.

Six of them rotate the plane of plane-polarized light to the right, and one rotates the plane of plane-polarized light to the left.

A racemic mixture containing equal amounts of d-enantiomer and l-enantiomer has no effect on the plane of plane polarized light.

For purposes of this invention, when determining whether a compound is dextrorotatory or levorotatory, the effect of the compound on light at a wavelength of 5893 Armstronges (the so-called D-line of sodium) should be considered.

A moiety of formula (A) is considered dextrorotatory if the hydrochloride salt of the free base of formula (AH) rotates the light to the right.

As described in West German patent application P 2822465.9, the following reaction formula is racemic 4a/9b of formula (■)
-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (in the formula
1 and Yl are as described above).

2 The preferred group for is benzyl for economic reasons.

but, Other groups also play a role in the above reaction scheme. It will be clear to those skilled in the art that

Examples of other groups for R2 include those in which the benzyl moiety's benzene ring is substituted with, for example, one or more of methyl, methoxy, nitro and phenyl, and benzhydryl.

As described in more detail in DE 2822465.9, the free base of formula (■) also serves as a precursor for the compound of formula (n) and is illustrated by the reaction scheme below.

In the formula, 21 and n are as defined above.

The acid of formula (IX) or the corresponding acid chloride or acid bromide is used to acylate compound (■) to form the intermediate of formula (X).

The intermediate of formula (X) was then reduced with lithium aluminum hydride to yield the desired compound of formula (II).

Using reagents and conditions known to selectively convert secondary alcohols to the corresponding ketones, formula (I
oxidizing the compound of I) (wherein 21 and n are as defined above).

) Examples of such oxidizing agents that can be used in this reaction are potassium permanganate, potassium dichromate and chromium trioxide, with the preferred reagent being chromium trioxide in the presence of pyridine.

As will be clear to those skilled in the art, formulas (IV) and (■)
The 4a,9b-trans-compound forms a single racemate, which can be divided into a pair of enantiomers, one of which is dextrorotatory and the other levorotatory.

4 of formula (n) having another asymmetric carbon in the 2-1 substituent
The a.9b-trans compound forms two diastereomers, and each diastereomer can be divided into dextrorotatory and levorotatory enantiomers.

5-aryl-2.3.4.4a.5.9b hexahydro-IH-pyrido [4.3-b) indole moiety (A)
It has been found that the above-mentioned compound, which is dextrorotatory, has an effect as a tranquilizer.

Corresponding compounds in which moiety (A) is levorotatory have significantly less activity.

While the nature of the 21 substituent attached to moiety (A) is important for optimal purification stabilizing effect, the stereochemistry of the 21 substituent is less important.

Thus, a compound of formula (m) in which moiety (A) is dextrorotatory is of formula (CH2).

It is highly active whether the 2-substituent of CHOHC6H5Z1 is racemic, dextrorotatory or levorotatory.

The compound of formula (■), as commonly obtained by the above method, is a mixture of diastereomers.

Methods for separating such mixed diastereomers are by fractional crystallization and chromatography.

Separation by fractional crystallization of the mixed orastereomer of formula (II) is sufficient to obtain each of the above diastereomers in high purity.

Of course, column chromatography can be used to further purify diastereomers.

Solvent systems useful for fractional crystallization of the diastereomers described above are, for example, mixed solvent systems containing both polar and non-polar solvents.

Examples of such polar solvents are ethyl acetate, methanol, ethanol, acetone and acetonitrile.

Examples of such non-polar solvents are hexane and its close homologues, hexane, toluene and carbon tetrachloride.

A preferred mixture of such solvents is ethyl acetate and hexane.

The resolution of a single diastereomer of formula (I) into the d- and l-enantiomers can be carried out by various methods well known for the resolution of racemic amines.

F 1eoeret al” Reagents f
orOrganic 5ynthesis”, Will
ey E 5ons.

■nc0, New York (1967), Vol.
,I.

See P977 and the literature cited therein.

However, a particularly useful method of obtaining enantiomers from the racemate of formula (I) is to esterify the compound of formula (II) with an optically active acid and separate the diastereomeric esters by fractional crystallization or chromatography.

The enantiomeric ketone of formula (■) is then obtained by oxidation of the corresponding enantiomer of formula (II).

Various optically active acids are known for such uses (
However, it has been found that L-phenylalanine is particularly useful for resolving diastereomers of formula (II).

An alternative method to obtain enantiomeric compounds of formula (II) is to obtain enantiomeric compounds of formula (II)
(2) by stereospecific synthesis in which the resolved enantiomers of the tricyclic secondary amine are condensed with the enantiomeric precursor of the substituent at the 2-position.

In order to carry out the stereospecific synthesis of compounds of formula (II), a novel method using split reactants to advantageously achieve this objective and obtain high yields of optically pure compounds is described below. Abbreviated.

Of course, this method is also useful for obtaining racemic products when carious reactants are used.

In the reaction formula, Zl and n are as defined above, and q is 1 or 2.

Optical isomers of formula (■) are obtained by resolution of racemates.

This resolution is effected by the salt formed between the amine (■) and the optically active acid.

Although a variety of acids are known that are useful for resolving amines (see, e.g., F 1eser et al., supra), a preferred acid that readily separates amines (■) is the optical isomer of N-carbamoylphenylalanine ( D- and L-)
It is.

It is obtained by reacting the isomeric phenylalanine with sodium cyanide in a manner known to those skilled in the art.

This resolution is carried out by reacting one of the isomeric N-carbamoylphenylalanines, for example the L-isomer, with an equimolar amount of the racemic compound of formula (■) in the presence of a suitable reactive inert solvent to form a homogeneous solution of the above salt. Form.

Upon cooling, the salt of one of the optical isomers of formula (■) is obtained as a crystalline solid, which can be further purified if desired.

the mother liquor containing mainly salts of other isomers is evaporated to dryness;
partitioning the salt with a hydroxyl solution of a base such as sodium carbonate, potassium hydroxide or calcium carbonate and extracting the free base with a water-immiscible solvent, typically ethyl acetate;
Drying and evaporation of the solvent give a residue enriched in another isomer of the amine of formula (■).

This residue is taken up in a reaction inert solvent and an equimolar amount of other isomers of N-carbamoylphenylalanine, such as D-
isomer and the solution is cooled to precipitate crystals of another isomeric N-carbamoylphenylalanine salt of formula (■).

Salts containing a single enantiomer of amine (■) are each resolved as described above to yield pure dextro and levorotary isomers of formula (■), respectively.

As mentioned above, if enantiomeric compounds of formula (n) are to be obtained by the reaction of amines (■) and lactols (x[V), separated reactants are required.

In order to obtain the resolved isomers of formula (■), a resolution of the corresponding racemic mixture of oxyacid precursors of formula (■) is carried out.

The resolution of the racemic hydroxy acid (X[I) is the amine (■
), e.g. d-
The above salt is fractionally crystallized using ephedrine to precipitate one isomer of ■, the other isomer of ■ is precipitated together with the enantiomer of ephedrine, and the two salts are separated and ■
The dextro and levorotatory isomers of are obtained and each isomer is converted to lactol (XIV) as described above.

For the synthesis of each enantiomer of formula (II), the formula (
Equimolar amounts of the separated reactants of (2) and (XIV) are contacted under reductive alkylation conditions in the presence of a reaction-inert organic solvent.

A method for carrying out a reductive alkylation reaction is described, for example, by Emer.
son, Organic Reactions 4-
174 (1948) and Rylander” Ca.
talytic Hydrogenation 0ver
Platinum MetalsAcademic
press New York, 1967, p291
This will be discussed using the method reported by -303.

This reaction is carried out in the presence of catalytic amounts of various reducing agents useful for the reductive alkylation of secondary amines with aldehydes and ketones, such as noble metal catalysts such as platinum, palladium, rhodium, ruthenium or nickel; Cyano is carried out with metal hydrides such as sodium boronate, sodium borohydride and lithium borohydride; and formic acid.

Preferred reducing agents are noble metal catalysts and sodium cyanoborohydride.

These products are then isolated by standard methods and purified, if desired, for example by crystallization or chromatography.

The desired enantiomeric products are thus obtained in good yields and are optically highly pure.

Another suitable tranquilizer of formula (I) is a dextrorotatory amine (
(2) and racemic lactol (XIV) according to the above method.

The products of formula (II) are optically active based on the polarizing power (chirality) of the amine moiety (A) as defined above.

It is a highly active tranquilizer and also serves as an economical intermediate for oxidation to the ketone product of formula (IV) by the above method.

Other starting compounds besides the new intermediates of formula (■) and (xrv) are commercially available, their preparation methods are clearly reported in the chemical literature, and can be prepared by methods known to those skilled in the art.

For example, phenylhydrazine is commercially available or as described by Wagner and Zock, “5ynth
etic Organic Chemi 5try”,
John Weley & 5ons, New Y
ork, NY, 1956, Chapter 26, the 1-monosubstituted-4 piperidone is a commercially available reagent;
McElvain et al. J. Am
, Chem, Soc, 70.1826 (1948
) and the desired 3-benzoylpropionic acid and 4-benzoylbutyric acid are commercially available or manufactured by 'OrganicSynthesis', Co1
1, Vol, 2, John Wiley &5
ons, New York, NY, 1943, p.
Produced by a modification of the method of No. 81.

As mentioned above, the compounds of formula (I) have therapeutic uses as tranquilizers.

This tranquilizer of formula (I) is characterized by the reduction of schizophrenic symptoms in humans such as hallucinations, hostility, suspiciousness, emotional and social autism, anxiety, agitation and tension.

A standard method for detecting and comparing the tranquilizing activity of this series of compounds, with excellent correlation to efficacy in humans, is antagonism of amphetamine-induced symptoms in rats, A., Weissman et al., J. Pharma.
col, Exp, Thero, 151.339 (196
6) and Ouinton, et, al,, Na
ture, 200.178, (1963).

Recently, Leyson et al.
, Pharmacol, 27.307-316 (
Another method reported by (1978) is the inhibition of 3H-spiroperidol binding to dopamine receptors, which correlates with the relative pharmacological potency of drugs to influence dopamine receptor-mediated behavior. There is a relationship.

Gamma-carbolines and their pharmaceutically suitable salts useful as tranquilizers can be administered as a single therapeutic agent or as a mixture of therapeutic agents.

Although these compounds can be administered alone, they will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical techniques.

It can be administered orally in the form of tablets or capsules containing adjuvants such as, for example, starch, lactose or certain types of clay.

It can be administered in the form of elixirs or oral suspensions of the active ingredient in combination with emulsifying and/or suspending agents.

These compounds can be injected parenterally, for which purpose they or their appropriate derivatives are prepared in the form of sterile aqueous solutions.

Such aqueous solutions may be made isotonic by suitably buffering, if necessary, and by adding physiological saline or other solutes such as glucose.

Although the compounds of formula (I) are used for the treatment of mammals in general, the preferred patient is humans.

Ultimately, the physician will determine the optimal dosage for each individual patient, and the dosage will depend on the individual patient's age, body weight, and response, as well as the nature and severity of symptoms and the pharmacodynamics administered. It changes depending on the characteristics of

Generally, small doses are initially administered and the doses are gradually increased until the optimal dose is determined.

When the composition is administered orally, large amounts of active ingredient are required to achieve the same level of effect produced by small amounts of active ingredient administered parenterally.

Considering the above points, the daily dose for humans of the compounds of this invention is about 0.1-11001n, preferably 0.5-11001n.
25 mg would effectively stabilize the mind.

In individual cases in which the compounds of the invention have a long-term effect, the dosage is 5 to 125 μl per week, administered in one or two divided doses.

This value is an example for explanation, and in individual cases, a smaller amount or a larger amount may be better.

The following examples are intended to illustrate the invention without limiting it, and many variations are possible without departing from the scope of the invention.

Reference example 1 di-4 lance-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-IH-pyrido[4,3b]indole A, 40wLJ of toluene Medium 5.6′? (12,4 mmol) of dl-trans-8-fluoro-5-(p-fluorophenyl)-2-C4-hydroxy-4-(p-fluorophenyl)butyl]-2.34-4a.5-9b
5.3 mg (55,7,: IJ mol) of ethyl chloroformate was added to the solution of -hexahytoD-IH pyrido[4.3-b]indole.

The resulting mixture was refluxed overnight and then evaporated to dryness over L. to give a residual resin.

To this resin was added 200 ml of a mixture of ethanol and water in a volume ratio of 9:1.

Dissolve the resinous material, add 15f of potassium hydroxide,
The resulting mixture was refluxed overnight.

The solvent was evaporated in vacuo and the residue was partitioned between water and chloroform.

The organic extract was washed with water, dried with sulfuric acid),
Evaporated to dryness.

The residual oil was taken up in ethyl acetate and passed through a silica gel column, eluting with ethyl acetate to first remove by-products and then with a mixture of ethyl acetate and methanol in a 1:1 volume ratio to yield the desired product. Ta.

Fractions containing the title compound were combined and evaporated to dryness to give 1.51 (43%) as a yellow resin.

When this was allowed to stand still, crystals with a melting point of 115-117°C were formed.

B. Alternatively, di-h lance-2-benzyl 8-fluoro-5-(p-fluorophenyl)2.3.4.4
a.5.9b-hexahydroIH-pyrido [4.3-b
] Indole hydrochloride was refluxed in the presence of excess ethyl chloroformate or methyl chloroformate, isopropyl or n-butyl, then hydrolyzed and treated as above to give the title compound.

Reference example 2 A,D(-)-N-carbamoylphenylalanine 75
To a suspension of 16.52 P (0.10 mol) of D(carphenylalanine) in water was added 12.=1 (0.10 mol) of sodium carbonate hydrate.

To this solution was added 12.17 f (0.15 mol) of potassium cyanide with stirring and the mixture was heated on a steam bath (internal temperature 85-90° C.) for 15-2.0 hours.

After cooling in a water bath, the reaction mixture was carefully diluted with concentrated hydrochloric acid in pf (
Acidified to 1-2.

This precipitate was collected, washed with ice water, and washed with ethyl ether to obtain crude product No. 151.

Dissolve this in 250ml of warm methanol and 400rIL
It was recrystallized by diluting with 1 liter of water, slowly cooling to room temperature, and then refrigerated with 1 liter of water until precipitation was complete.

The product was obtained as white opaque needles in a yield of 58%.

Melting point 203-204℃ (decomposed), [α] -40.7
° (methanol).

B, L(-1-)-N-J Rubamoylphenylalanine In A above, L-(→phenylalanine was used instead of the D(+)-isomer to produce L(-N-carbamoylphenylalanine with a yield of 42%). I got the rate.

Melting point 205-207°c (decomposition) Ca)", g(
−+) 39.0° (methanol).

Example 1 dl -trans-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3b]indole A, N-1 Rubamo Resolution of ylphenylalanine enantiomeric salt ■, dl-trans- dissolved in a minimum amount of ethanol
8-Fluoro-5-(p-fluorophenyl)-2,3
・4.4a・5.9b Hexahydro-IH-pyrido [4
・3-b] Add 1 equivalent of L(- to the equivalent of indole free base)
1-) Addition of N-carbamoylphenylalanine.

This mixture was heated on a steam bath.

During this time, more ethanol was added until a solution of the product was obtained.

The solution was cooled to room temperature and the precipitated free base (@
White needle-like crystals of enantiomeric L(+)N carbamoylphenylalanine salt were collected and dried to obtain a product with a melting point of 207-209°C (α) 5.9° (meth/-ol). .

2 Evaporate the mother liquor obtained above to dryness and carbonate the residue)
Partitioned between aqueous IJum solution and ethyl acetate, the organic layer was dried over magnesium sulfate and evaporated in vacuo to give a residual oil.

This oil was dissolved in a small amount of ethanol and an equivalent amount of LJ (
The reaction with N-carbamoyl phenylalanine was carried out.

The mixture was warmed on a steam bath while additional ethanol was added until complete solution.

The solution was cooled and worked up as described above to give the free base crude enantiomer D(→-N-carbamoylphenylalanine salt in 92% yield.

This was recrystallized from ethanol (75ml/?) with a total yield of 65% and a melting point of 209-211'C, Cα〕♀-+66
A product of ゜(methanol) was obtained.

B. Separation of Enantiomeric Free Base Hydrochloride Salt The enantiomeric N-carbamoylphenylalanine salt obtained in A.1 was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate and the organic layer was dried over magnesium sulfate without heating. It was concentrated in vacuo.

The residual oil was dissolved in ethyl ether (50-100rrLJ/
? ) and dry hydrogen chloride gas was swirled over the surface of the solution to obtain a white precipitate.

Excess hydrogen chloride and ether were distilled off at room temperature under reduced pressure to give (@-trans-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-IH- Pyrido[4,3-b]indole hydrochloride about 9
Obtained with a yield of 6%.

This was recrystallized by dissolving it in a minimum amount of boiling ethanol and adding ethyl ether until the solution became cloudy.

The product was obtained as small white crystals (75% recovery), melting point 258-260'C1 [α]♀(-) 40.9° (methanol) at 2°. (quadrans-8-fluoro-5-(p-fluorophenyl)-2, 3, 4,
4a, 5, 9b hexahydro-1H-pyrido [4, 3-
b] Indole was obtained with a yield of 96%, recrystallized with a recovery rate of 75%, melting point 260-2625℃, [α] back (Kawa 39
, 2° (methanol) product was obtained.

Claims (1)

[Claims] A racemic mixture of formula 1 (in which the hydrogen atoms added to the carbon atoms at positions 4a and 9b are in a trans relationship with each other) is reacted with the D or L-isomer of N-carbamoylphenylalanine. A method for producing a dextrorotary isomer of the above formula, characterized in that the salt is separated and subsequently decomposed to form a mixture of salts.2. Process according to claim 1. 3. A patent claim characterized in that the decomposition of the separated salt is carried out by reaction of the salt with an aqueous base solution, and the resulting free base is extracted using a water-immiscible solvent. range 1
4. The method according to claim 3, wherein the water-immiscible solvent is ethyl acetate.